Tag Archives: articles

november 2017, Techniques

Top Techniques: Single-Cell RNA Sequencing

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Image from Papalexi E & Satija R, Single-cell RNA sequencing to explore immune cell heterogeneity. Nat Rev Immun (2017).

As scientists ask increasingly focused and nuanced questions regarding cellular biology, the technology required to answer such questions must also become more focused and nuanced. In the last decade, we have already seen several significant paradigm shifts in how to process data in a high-throughput manner, especially for genomic and transcriptomic analyses. Microarrays gave way to next-generation sequencing, and now next-generation sequencing has moved past bulk sample analysis and onto a new frontier: single cell RNA sequencing (scRNA-Seq). First published in 2009, this technique has gained increasing traction in the last three years due to increased accessibility and decreased cost.

So, what is scRNA-Seq?

As the name suggests, this technique obtains gene expression profiles of individual cells for analysis, as opposed to comparing averaged gene expression signals between bulk samples of cells.  

When and/or why should I use scRNA-Seq compared to bulk RNA-Seq? What are its advantages and disadvantages?

The ability to examine transcriptional changes between individual cells uniquely allows researchers to define rare cell populations, to identify heterogeneity within cell populations, to investigate cell population dynamics in depth over time, or to interrogate nuances of cell signaling pathways—all at high resolution. The increased specificity and subtlety given by single-cell sequencing data benefits, for example, developmental biologists who seek to elucidate cell lineage dynamics of organ formation and function, or cancer biologists who may be searching for rare stem cell populations within tumor samples.

Practically, scRNA-Seq often requires far less input material than traditional bulk RNA-Seq (~103-104 cells per biological sample, on average). The trade-off for this downsizing advantage, however, is because of the lower input, there is often more noise in the output data that requires additional filtering. Also, as with any rising star high-throughput technique, standardized pipelines for bioinformatics processing of the raw output data are still being finalized and formalized. As the same type of growing pains occurred when bulk RNA-Seq rose to prominence, no doubt a more final consensus will also eventually be reached for scRNA-Seq.

What platforms are used for scRNA-Seq?  

The three most current and common workflows to isolate single cells for sequencing are by microplates, microfluidics, or droplets.

Microplate-based single cell isolation is carried out by laser capture of cells, for example by FACS, into wells of microplates. This approach is useful if there are known surface markers that can be used to separate cell populations of interest. It also provides the opportunity to image the plate and ensure that enough cells were isolated and that it was truly a single cell isolation. Reagents for lysing, reverse transcribing, and preparing libraries are then added to individual wells to prepare samples for sequencing.   

Microfluidics-based single cell isolation consists of a chip with a maze of miniature lanes that contain traps, which each catch a single cell as the bulk cell mixture is flowed through. Once cells are caught within the traps, reagents for each step of the sample preparation process (lysis, reverse transcription, library preparation) are flowed through the chip lanes, pushing the cell contents and subsequent intermediate materials into various chambers for preparation, followed by harvesting the final material for sequencing.

Droplet-based single cell isolation also uses microfluidics but instead of traps it involves encapsulating, within a single droplet of lysis buffer, (1) a single cell and (2) a bead linked to microparticles, which are the reagents necessary for sample preparation. The advantage of this approach is that a barcode can be assigned to the microparticles on each bead, and thus all transcripts from a single cell will be marked with the same barcode. This aspect allows pooling of prepared samples for sequencing (decreasing cost) as the cell-specific barcodes then can be used to map transcripts back to their cell of origin.

The other significant consideration for designing scRNA-Seq experiments is what sequencing method to use. Full-length sequencing provides read coverage of entire transcripts, whereas tag-based sequencing involves capture of only one end of transcripts. While the former approach allows for improved mapping ability and isoform expression analyses, the latter allows for addition of short barcodes (Unique Molecular Identifiers, UMIs) onto transcripts that assist in reducing noise and bias during data processing.    

So, which platform should­ I use?

As with most advanced techniques, determining which platform to use depends on the biological question being asked. A microplate-based platform does not accommodate high throughput analyses but does allow for specificity in what types of cells are being analyzed. So, for example, it would be a good choice for investigating gene expression changes within a rare population of cells. It also does not require particularly specialized equipment (beyond a FACS machine) and thus is a relevant choice for researchers without access to more sophisticated options. Microfluidics-based platforms are capable of more throughput than microplate-based while retaining sensitivity, but they are more expensive. Finally, droplet-based platforms provide the greatest amount of throughput but are not as sensitive. Thus, they are most appropriate for elucidating cell population composition and/or dynamics within complex tissues.

How can my scRNA-Seq data be processed, and is it different than bulk mRNA-Seq data processing?

Performing computational analysis on scRNA-Seq data follows a similar pipeline as bulk RNA-Seq, though there are specific considerations required for scRNA-Seq data processing, especially during later stages of the pipeline. One of the major considerations is significant cell-to-cell discrepancies in expression values for individual genes. This effect occurs because each cell represents a unique sequencing library, which introduces additional technical error that could confound results when comparing cell-specific (and therefore library-specific) results. This effect can be mitigated during data processing by additional normalization and correction steps, which are included in most of the publicly available scRNA-Seq processing pipelines.

Finally, the types of interpretations drawn from scRNA-Seq experiments are also technique-specific and question-dependent. Common analyses of scRNA-Seq data include clustering, psuedotime, and differential expression. While clustering is done with bulk RNA-Seq data, clustering scRNA-Seq data allows for assessing relationships between cell populations at higher resolution. This aspect is advantageous for investigating complex tissues—such as the brain—as well as for identifying rare cell populations. Given the large sizes of scRNA-Seq data sets, performing clustering of scRNA-Seq often requires dimensionality reduction (i.e. PCA or t-SNE) to make the data less noisy as well as easier to visualize. By coupling clustering results along with differential expression data, identifying gene markers for novel or rare populations is made easier. Psuedotime analysis is particularly useful for scRNA-Seq experiments investigating stages of differentiation within a tissue. Using statistical modeling paired with data reflecting a time course (for example, various developmental stages of a tissue), this analytical method tracks the transcriptional evolution of each cell and computationally orders them into a timeline of sorts, thus providing information relevant for determining lineages and differentiation states of cells in greater detail.  

Where can I do scRNA-Seq in Boston?  

Tufts Genomics Core here at Sackler has a Fluidigm C1 machine (microfluidics). Harvard Medical School (HMS) has several options for single-cell sequencing platforms. HMS Biopolymers Core also has a Fluidigm C1 system that is available for use on a for-fee, self-serve basis after training, with reagents purchased and samples prepared by the individual, as well as a 10X machine (droplet). HMS Single-Cell Core has a inDrop machine (droplet) that includes for-fee full service with faculty consultation.

What is the future for scRNA-Seq?

Bettering the way in which samples are processed and data is analyzed is a priority for scRNA-Seq experts. Specifically, ongoing work seeks to improve library preparation and sequencing efficiency. The programs used to process scRNA-Seq data are also still in flux so as to provide better normalization and correction tools for increasingly accurate data. On a larger scale, developing technology to analyze other biological aspects (genomics, epigenomics, transcriptomics) at the single cell level is of high interest, especially when considering how powerful combining these other forms of single-cell analysis with transcriptomics could be for understanding both normal and disease biology.

Resources:

  1. scRNA-Seq software packages: https://github.com/seandavi/awesome-single-cell
  2. Review of bioinformatics and computational aspects of scRNA_Seq: https://www.frontiersin.org/articles/10.3389/fgene.2016.00163/full
  3. Practical technique review: https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-017-0467-4
  4. Start-to-finish detailed instructions on scRNA-Seq: https://hemberg-lab.github.io/scRNA.seq.course/biological-analysis.html
articles, September 2017

New Sackler leadership envisions training to career excellence

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The beginning of this academic year has seen a shift in the leadership of the Sackler school with the retirement of both the Dean & the Associate Dean. Dr. Naomi Rosenberg’s decision to retire from her role as the Dean of Sackler after 13 years of dedicated service was received with a mixture of surprise and trepidation, which was compounded by Associate Dean Kathryn Lange’s retirement decision around the same time. The dynamic duo left large shoes to fill and the search committee spent the summer choosing candidates who would have the school and its constituents’ best interests in mind. To that end, Daniel Jay, Ph.D., a faculty member of the Developmental, Chemical & Molecular Biology department, and Daniel Volchok, Ed.D., previously the Assistant Dean for Graduate Student Life at Northeastern University, were chosen to fill the positions of the Dean and Associate Dean, respectively. Both of these individuals bring their extensive experiences to the table. Dean Jay has mentored numerous graduate students and has served as the post-doc officer for the school prior to his appointment as the Dean, and Assoc. Dean Volchok has worked with both undergraduates and graduate students across multiple disciplines that range from medical schools to business schools.

For Dean Jay, a fortuitously timed conference on graduate education solidified his commitment to throw his hat in the ring, while Assoc. Dean Volchok found that beginning his position simultaneously with a new Dean was a wonderful opportunity to build a fresh vision for Sackler from the ground up. Aside from similar serendipitous timing, Jay and Volchok also developed convergent objectives for how to keep Sackler and its associated graduate programs a competitive academic institution. Of particular interest regarding these new goals is that they grew directly out of interactions with students.

“In my interview, with the students I met with, they all talked about career,” Volchok recalled. “It was very important to the students. It turned out they were right…career focus is part of the life here.”

Jay states that their new mission for Sackler is one of “training to career excellence”, which encourages high distinction not only at the bench for students, but also in less traditionally academic contexts, such as in the boardroom or at the news desk. “The reason for that,” Jay explained, “is that 80% of our trainees go on to careers beyond academia…and we need to train all of those individuals in addition to the small number that do go on in academia to compete, to excel, and to lead in areas of whatever their chosen career passion.”

Both Jay and Volchok believe that trainees are the key to Sackler’s success. To highlight the importance of student leadership, Jay mentions that “extracurricular programs, that didn’t exist 10 years ago, were developed by student leadership such as the GSC [Graduate Student Council], TBBC [Tufts Biomedical Business Club] and the PDA [Postdoctoral Association].” They both want to see this trend to continue as they would like students to take ownership of their career choices and approach the Dean’s office with their needs and wants to ensure their success. Jay believes that “we will be stronger and better if we are willing to change with the times to provide what students require for success.” He is also less concerned that faculty may not be on board with non-traditional career choices. He believes that most faculty are not opposed to career choices outside of academia, and he stresses that research excellence is still the first priority for any trainee at the Sackler school and will not be compromised

In his twenty years at Tufts, Jay has watched, as well as aided, the trainee community forge extracurricular programs and initiatives to fulfill these alternative training needs, despite, and more aptly because of, the shortage of accessible resources. To build upon this foundation, this fall semester the Dean’s office launched two new trial initiatives: a drug development short course, taught by alumnus Stefan Gross, and career counseling services provided by Sarah Duncan. In addition, Volchok is currently working on developing a business skills course based on his experience in Northeastern’s business school; such action speaks to the fresh perspectives he brings to Sackler through his extensive and varied educational and administrative experience. While this type of career training will remain supplemental in the short-term, they plan to eventually incorporate such training directly into the infrastructure of Sackler. This integration will run the gamut from admissions to available curriculum, such as proposed course offerings focused on business or transferable skills (eg – team building, project management, etc.), school-facilitated industry internships that are integrated into a student’s research plan, and possibly a two-year biomedical Masters program that would incorporate training in both research and non-traditional science career development.

The majority of these programs will be accessible not just for graduate students but also for Tufts postdocs as well. Jay’s role as the post-doc officer for the school has made him very much aware of the bottleneck effect of the current academic job crisis that these postdocs face. Therefore, he has stressed that programs be made open to the whole Sackler community whenever possible. He also proudly mentions the success of the PDA, which organized around 70 events last year, and affirms his faith in trainee leaders to build career-related programs. Unfortunately, industry internships will not be open to postdocs, but Jay hopes to work with industry contacts to improve that situation.

The success of these programs and the new vision, according to Jay, will be evaluated by whether “graduates have an easier time finding their first job.” He mentions that he developed this milestone after his conversations with alumni who wished they had learned particular skills before entering the job market. In these conversations, he also discussed building more formal engagement between the alumni and the school, such as the possibility of alumni acting as adjunct professors to teach aforementioned short courses and the development of a biomedical research interest group. He affirms that he has had a positive reaction from the alumni who have also expressed interest in hosting/organizing events. He also mentions that alumni would definitely be a part of the new branding strategy now that the Dean’s office has developed its new mission. As a key component to executing these varied goals, Jay and Volchok have also established and seeded a new Sackler career development fund, dedicated to financing the programming to come out of this new mission.

Jay and Volchok aim to use their first year to launch programs that would serve as “trial balloons.” The school is “small, so [it is] easy to make changes”, according to latter, and therefore, they would like to test out which programs can be expanded upon in the long term. “This year will test the viability and utility of these short courses that can be used to build upon for longer term goals, and student engagement and participation will be crucial to seeing these initiatives succeed,” Jay elaborated. This last point seems to be critical to the new administration, as “feet on the ground”, as Jay put it, will be the litmus test for whether these initiatives continue. Both seemed confident that the students will indeed engage, given how proactive the trainee community has been about this topic in the past, and are ready and willing to listen to individual feedback.

“We’re of the size that we can make sure students are successful,” Volchok observed. “We can work with individual students when we need to. Students can feel like part of the community and not just a number.”

While a small student body has organizational advantages and new approaches can be tested easily without much bureaucratic repercussions, there are also disadvantages. The current funding climate, along with the fact that Sackler is surrounded by heavyweight schools with similar programs, has led to a dwindling number of students recruited to our programs every year. In the light of such events, concerns regarding the continuity of Sackler as a successful graduate school are bound to rise. However, both Jay and Volchok believe that their new mission of a strong emphasis on career development will help Sackler stand out amongst the other schools in the area.

“I view this as our route to success…how do we define ourselves in a very competitive environment,” Jay said. “If we dedicate ourselves wholeheartedly to this mission, we would, in some ways, distinguish ourselves so that we are competitive, so that a student may choose us because they seek this path toward career excellence. We have to find a way to be relevant…I think the combination of being in Boston, of being small and mobile–if we can do it, we set the standard for the rest of the country. So that is exciting to me, and that’s making a difference, and this is why I’ve taken this job.”

Besides the strong emphasis on career development, the Dean’s office’s new mission also prioritizes community building both in and outside of Tufts. Jay mentions a great advantage that Sackler has by being surrounded by Medical, Dental and Nutrition schools, and being in the same university as a Veterinary school–all opening doors to an influx of opportunities for trainees and faculty to design their studies that could result in more collaboration within the school. As an example, he cites the Clinical & Translational Science Institute (CTSI) and their intentions of working more with the Sackler Basic Science programs (CTSI currently offers drop-in hours for statistics consultation and also offers a course on biostats, both of which are open to Sackler trainees). Jay is also looking forward to hearing individual programs’ changes to curriculum based on discussions between students and faculty mentors (CMDB is offering a bioinformatics class to its students after it was brought up in the program retreat). Additionally, Jay hopes to reach out to industry as well for more collaboration on various fronts.

Jay and Volchok are also tuned in to the social needs of the community to protect its members while reaching outside of their bubble. They are both advocates of the new student club Scientists Promoting Inclusive Excellence @ Sackler (SPINES), and stressed “increased awareness of diversity and inclusion” and building a tolerant community. In an effort to increase student engagement, Volchok has revised The Goods–a weekly digest of news, opportunities and events both on and off campus–delivered to the school community. He believes that “students have a good voice here” and are great resources on how the school and its environment can be improved. Both Jay and Volchok mentioned the need for more community outreach into middle schools, both in the Chinatown communities and the African-American communities in Roxbury. They would like the students to help with organizing and mentoring in these communities.

Of course, most of these ideas are still in the very early stages. “We’re at the very beginning of all this,” Jay said with a laugh. Even so, they seem to be off to a good start, as Jay and Volchok spent their first few weeks listening to the needs of the community before shaping their mission. Jay admits “…the level of concern and frustration of career path thing is here,” an issue frequently brought up by students in the past. Jay and Volchok are committed to listening to the needs of the trainees and helping them as much they can, but they also want the students to take ownership of their own career paths by being proactive. When asked what the students can do to help the Dean’s office, Volchok expresses his eagerness to work with students to improve their experience at Sackler. “Be open and honest with us. Come and tell us when things are going well. Come and tell us when things are not going well. If you have ideas and things we can do differently, let us know.”

articles, Community, September 2017

Greentown Labs is at the Forefront Boston’s Cleantech Industry

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In the wake of hurricanes Harvey and Irma, I feel compelled to understand what cleantech strategies are currently available to tackle climate change. California’s cleantech industry was an obvious thought that came to mind. Over the past decade, California’s institutions and companies have been leaders in the U.S. market for producing clean energy and biodegradable materials. This past summer, the Joint BioEnergy Institute (JBEI) in the Bay Area received federal funding for innovation in biofuels and bioproducts. Since its inception, JBEI has yielded several startups that are committed to engineering microbes and crops to convert sugars into high-value renewable fuels. But where does Massachusetts stand in the cleantech industry? Fortunately, we’re not too far behind.

The nation’s largest cleantech startup incubator actually exists right here in Massachusetts. The Somerville incubator Greentown Labs hosts more than 100 startup companies and has raised over $200 million in investor funding since its founding. There is an emphasis on solar, wind, and wastewater technology in this incubator that is very unique. For example, the startup WrightGrid has developed a single solar-panel-based charger for robust cell phone charging in rural areas. Furthermore, SolChroma has developed full-color reflective digital billboards that reduce light pollution and energy costs in big cities. The company Sistine Solar can come to your home and design personalized solar panels in all aesthetic shapes and colors, enticing homeowners to switch to solar energy. One company that piqued my interest was Spyce, a startup intersecting food and technology. The company has developed a robotic kitchen that can serve meals with fresh ingredients in less than five minutes. The robotic kitchen is compact and reduces the amount of space and manpower that is typically needed at restaurants to prepare meals.

For the global market, Greentown Labs hosts Promethean Power Systems, a company that manufacturers rural refrigeration systems in off-grid and partially electrified areas of developing countries. In the same vein, Ivys Energy Solutions provides renewable hydrogen fuel cells to the international market. For the agrigulture sector, Raptor Maps fuses drone-based imaging technology to detect pest and weed infestation so to reduce water usage and nutrient management. Multisensor Scientific has also developed imaging capabilities to visualize and quantify in real-time methane leaks from natural gas infrastructures, thus reducing harmful methane emissions that are driving climate change. In the materials sector, Alkemy Environmental recycles industrial waste into lightweight concrete. For water management, Aquafresco is reinventing how we do laundry through a wastewater recycling invention that reduces the amount of water we use by 95%

Just a week ago, Tufts University collaborated with Greentown Labs to support cleantech solutions. The agreement between the parties will allow them to share their expertise, resources, and networks. The collaboration is also exciting because it allows for startups run by Tufts affiliates to directly become members of Greentown Labs. Currently Greentown Labs is tight on space but they are opening up a new building in Somerville next month to host more startups. The expansion of Greentown Labs is very promising for the future of cleantech in the Boston area. Just like Kendall is synonymous with biotech, in the next few years Somerville will be synonymous with yuppies, hipsters, and, perhaps, cleantech.

References:

http://www.xconomy.com/san-diego/2017/06/19/synthetic-genomics-breakthrough-algae-produces-twice-as-much-oil/#

 

https://now.tufts.edu/news-releases/tufts-university-collaborates-somervilles-greentown-labs-support-inventive-clean

 

https://www.wheretraveler.com/boston/eat/boston-food-tech-future-just-got-delicious

 

https://www.greentownlabs.com/about/

 

http://newscenter.lbl.gov/2017/07/17/doe-renews-jbei-funding/

articles, Library, Notes from the library, September 2017

Notes from the Library…Introducing JumboSearch

In June, Tufts Libraries launched a new iteration of our search platform, JumboSearch.  This means that the way you search for resources (books, journals, databases, articles, etc.) available through our libraries has changed.  This new search platform is part of our transition to a new integrated library system, which will improve how we manage our resources.

Here is a brief primer on how to use JumboSearch to find the resources you need.

How do I access JumboSearch?

The search box at the center of the Hirsh Health Sciences Library homepage (https://hirshlibrary.tufts.edu/) is for JumboSearch.

How do I find a book in JumboSearch?

Enter a title, author or keyword in the search box at the center of the Hirsh Health Sciences Library homepage.  Use the filters on the left side of the results page to limit your search to books.  Once you find the book that you need, click the title to view additional information, such as location and availability, and, if it is available electronically, access the full text.

What if the book I want is located at another Tufts library?

If the book is located at another Tufts library, then click the title of the book on the JumboSearch results page.  Select the ‘Log in’ link in the yellow bar at the center of the page.  Once you have signed in with your Tufts username and password, click the ‘Request item’ link to request delivery of the book to the Hirsh Health Sciences Library.  You will receive email notification when the book is ready for you to pick up at our Library Service Desk.

How do I find a journal? 

Enter the title of a journal in the JumboSearch box at the center of the Hirsh Health Sciences Library homepage.  If the journal is available through our libraries, then the title should appear at the top of the results.  Click the title of the journal to view print and electronic availability.

Another (and I find more efficient) method of finding a journal is to click the ‘Journals’ tab at the top of any JumboSearch page, which brings you to a page where you can search or browse our Journal list (versus all of our resources).

Can I use JumboSearch to find the full text of an article?

Yes!  If you have the title of a journal article and want to know whether or not the full text is available through Tufts, then copy and paste the title into JumboSearch.  If necessary, use the filters on the left side of the results page to narrow your results.  Once you find your article, click the ‘Full text available’ link.

How do I access my library account?

Use the ‘Log in’ link in the upper right-hand corner of any JumboSearch page, or in the yellow bar at the center of an item details page.  In your library account, you can see the items that you currently have checked out (including interlibrary loan books), requests, fines and blocks, as well as renew Tufts Libraries’ books.

articles, Events for Students, Library, Library Events, September 2017

Library Events: September & October

Stress Less, Learn More

Wed September 20th || 3-4 PM, Sackler 510

Register to attend in person  /  Register to attend via WebEx

 

Introduction to Citation Management

Tues September 26th || 9-10 AM, Sackler 510

Register to attend in person  /  Register to attend via WebEx

Wed September 27th || 3-4 PM, Sackler 510

Register to attend in person  /  Register to attend via WebEx

 

Show the Impact of Your Research

Tues October 3rd || 9-10 AM, Sackler 510

Register to attend in person  /  Register to attend via WebEx

Wed October 4th || 3-4 PM, Sackler 510

Register to attend in person  /  Register to attend via WebEx

articles, Community, May 2017

Notes from the North – Happy Mother’s Day!

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Anyone who has been to the supermarket or drug store in the last couple of weeks has been bombarded with commercial reminders that mother’s day is just around the corner. Flowers, mom mugs, and cards all vie for attention next to registers beckoning shoppers to make a purchase and check mother’s day responsibility off the to-do list. When I picked up a tea kettle printed with spring flowers for my own mother, I was thinking of it as a mechanism to express my gratitude for all the love and support she has lavished on me. Having recently produced my own offspring, however, I find myself reflecting on the truly amazing biological processes that must occur in order for us to be here to celebrate mother’s day. So in addition to thanking her for being the amazing person she is, I also thank her for embarking on an amazing biological adventure three decades ago.

The grind of assays, meetings, and deadlines often forces us to narrow our focus exclusively on our own little piece of the biological puzzle such that thinking about the larger pattern becomes overwhelming. This weekend I will be trying to contemplate the biology of motherhood with wonder and appreciation instead of my more typical bewilderment.

As med-bio researchers we are more attuned than most to the incredible number of steps that must take place in near perfect choreography for a healthy living organism to result. Dividing cells talk and cross-talk, differentiate at variable rates, and form functioning organs that allow the growing fetus to become more and more independent. For mammals, cross talk between the maternal system and the fetal system trigger additional developmental programs for lactation in mom that were arrested at puberty.  In the hood we are happy if we can get our cultures to remain viable for more than several months. With all the resources of a full organism, cells can still be fully functional decades later without resorting to preservation in liquid nitrogen!

Incidentally, there was a student at Stanford a few years back who was also moved by mother’s day to contemplate the science behind the celebration. He expressed his appreciation much more eloquently than I in a ballad that can be found here on YouTube.

This mother’s day take time to celebrate the positive impact your mother has had in your life and use it also as a day to celebrate eons of evolution that result in modern biology. And don’t forget father’s day and grandparent’s day too!

April 2017, articles, arts & culture, Community, Humans of Tufts Boston

Humans of Sackler: Patrick Davis, “I’ve been Accused of being a Science Robot”

Humans of Sackler, 23 March 2017

Patrick Davis, Neuroscience, Fifth-Year M.D./Ph.D. Student: “I’ve been Accused of being a Science Robot”

For this issue of Humans of Sackler, I had the opportunity to sit down with Patrick Davis, an M.D./Ph.D. student in the Neuroscience program. Although I see medical students coming and going around Sackler every day, I confess I haven’t gotten to know many of them – or much at all about the medical school curriculum. So it was a great pleasure to learn more about this from somebody who is as passionate about medicine as he is about science research; Patrick and I had a particularly engrossing conversation about the differences between these two kinds of higher education, and I hope you, dear reader, enjoy and benefit from it as much as I did!

 

Young Pat with the Chestnut Hill Academy Theoretical Physics Group

AH: How did you become interested in studying science?

PD: I had a physics teacher in 11th and 12th grade – Marty Baumberger – who was just the best teacher ever. He got me so into physics that I started a Theoretical Physics group at Chestnut Hill Academy… I went to Brown University as a physics major. I loved the open curriculum, but I was a terrible student. I didn’t do well my first year, so I switched to an economics major for about a year, and that was completely unfulfilling. Eventually I came to my senses and switched to biology… The thing about Brown: it’s chaos. There are no required classes, so you just mix and match and do whatever. There are requirements for your major, but you could theoretically never take a math class if you never wanted to. What happened to me was the best-case scenario: the first year and a half made me a more dedicated student. I learned that if I’m not doing something I really want to do then I’m going to be lazy, and if I don’t work hard then I’m not going to do well.

 

At a Macklis Lab get-together, chatting with friend and mentor Alex Poulopoulos (left)

AH: What was your first experience with neuroscience research?

PD: When I graduated from Brown, I didn’t know right away that I wanted to do med school or neuroscience. I ended up working at Jeff Macklis’s lab at Mass General Hospital for two years after college, and that was my first real exposure to neuroscience. Jeff made his name with a series of studies on induction of neurogenesis in the neocortex. I met Alex Poulopoulos there, who has been a mentor ever since, and a very good friend. I would credit Alex almost entirely with piquing my interest in neuroscience, but also with my development as a scientist. I love to come up with an idea, test it, go through the whole process myself, interpret my own data, talk to other people about their data – I like the actual scientific process. Alex just started his own lab at University of Maryland School of Medicine; anybody reading this, please apply to his lab! You could not ask for a better person to work for. He’s interested in how neural circuits self-organize, which is extremely interesting to me as well.

 

With pals from Brown University

AH: Why did you choose the M.D./Ph.D. path and how have your medical and scientific training differed?

PD: I could never be just an M.D. because I love science too much. The fundamental quality of a scientist is curiosity; medicine is more like service and helping people, curiosity about the people themselves, empathy. The preclinical years are a lot of memorization, but once you get into the hospital, it’s more like an apprenticeship. You’re learning how to do the day-to-day things that a doctor does: how to walk through clinical decision-making, interview a patient, present that information to other doctors, how to work with your hands if you’re doing a surgery rotation… Because medicine is an applied science, the goal there is all oriented around the health of the patient; I don’t think that’s really what science is about. For a long time, medicine has been done in a very parochial way: people in this hospital do it this way, people in another hospital do it another way. Evidence-based medicine still gets a lot of pushback. Take stenting for example: doing a coronary artery stent for someone with angina. About half of the stents in this country are done for stable angina – chest pain when you exercise, but not an acute threat to your health – and it’s now been shown over and over again that that is no better, and possibly worse, than just giving them statins and blood pressure reduction medication and telling them to eat their vegetables and exercise a little bit. It’s because doctors think in terms of, ‘I see it happen, it intuitively makes a lot more sense to me, so it must be this.’ Of course the lines are blurred in real life, but a true scientist would say, ‘We have to trust the evidence, why don’t we look at what’s causing the increased risk of doing the stent, or why do statins work?’ The curiosity that is absolutely necessary to be a good scientist is not necessary to be a good doctor… The types of mind that are selected for by these two professions are almost non-overlapping, they’re completely different.

 

Even science robots enjoy a night on the town every now and then

AH: What do you like to do when you’re not studying medicine or neuroscience, and how do you find the time and energy to do it all?

PD: I love to teach, I really like being in the didactic role and seeing people learn and discover things for themselves. I tutor for the MCAT, I used to tutor for the SAT, I’ve volunteered for things like middle school science fair mentoring and the Brain Bee. These kids in the Brain Bee were extremely impressive; they knew more facts for this test than I would have! Thomas Papouin and I also started a class trying to teach grad students the basics of the scientific method. There’s a whole rich history of how to think formally and scientifically; and the more aware you are of it and the more you practice it – like by applying these things to your own rotation project or qualifying exam – the better you get at it. The notion that, by just reading papers, this will happen – for some people, maybe it will, but the purpose of the program is to maximize the probability of this happening for everybody… I’ve been accused of being a science robot: the joke between Alex Jones and me is that when I get home, I have a scotch and read PubMed… The M.D./Ph.D.s that I’ve spoken to, the ones that succeed, are recharging one half of their brain while the other one works. Like a shark, like a science shark!

 

Relaxing by a picturesque mountain lake in the Cordillera Blanca, Peru

AH: Have you had many chances to travel outside of the U.S.?

PD: I’ve traveled through Europe a bit, I’ve been to Peru, Brazil… I was in Berlin at one point, and I decided to just hop on a train and go to Prague. I spent two full days and a night there, and it was awesome. Most of the people spoke English at tourist-type places, but it was fun to walk around, take pictures, be completely by myself… I had a Cormac McCarthy book called “All the Pretty Horses”, and it was nice just being on the train, reading or watching the sites, then walking around the city and going to a café for a coffee or beer. I don’t know much else about Prague, but aesthetically, I can’t imagine a prettier city. Part of why I enjoyed the city so much was because I didn’t expect it to be that way: of course when you go to Rome, you know that one of the greatest civilizations existed here and that every step you take is rich with history, but I didn’t expect this in Prague.

 

Enthusiastically sharing data at the Society for Neuroscience annual meeting

AH: What topic have you studied for your thesis work?

PD: Under Leon Reijmers’ mentorship, I’m trying to figure out how ‘extinction learning’ happens in the brain: it’s a medically-relevant type of learning that underlies treatment for psychiatric disorders like PTSD. In extinction learning, the patient repeatedly gets exposed to the thing they’re afraid of, you gradually increase the ‘stimulus intensity’, and they learn that it’s safe. So for example, if they’re afraid of spiders, you would show them a picture of a spider at first, then maybe have them in a room where there’s a spider in a corner, then work your way up to having them handle a spider. What I’ve found is that there’s a particular cell type in the amygdala – the parvalbumin interneuron – which acts a critical hub for this kind of learning: if you silence these cells, then you shut down the process of extinction learning. Now I’m using that finding as a jumping-off point to really figure out what’s going on. I’m manipulating parvalbumin interneurons with different frequencies of stimulation and seeing how the amygdala – and the rest of the brain – responds to that. It looks like I can ‘toggle’ the fear state up or down just by controlling this specific type of neuron!

 

Contemplating the mysteries of the universe

AH: Where do you see the field of neuroscience heading in the near future?

PD: I think that we have tools in neuroscience that 15 years ago, you couldn’t have even fathomed. Not just optogenetics, but recording techniques, chemogenetics, optical electrophysiology, simultaneous local field potentials with single units, closed loop systems… The engineers like Ed Boyden have done us a great favor. But now it’s time for us to step up. I think that in the next 2, 5, 10, 15 years there are going to be many, many discoveries that are really going to blow things open. Once we fall out of love with the mere application of modern tools to hypotheses we already kind of assumed to be true, then we’re going to ask the question: how? You have to record neurons’ endogenous activity, then do experiments that are really informative about what’s going on. In neuroscience, because we have these techniques, we can start asking this kind of question.

April 2017, articles, Events for Students

GSC Committee & Club Updates: April 2017

Tufts Biomedical Business Club (TBBC)

from Aaron BernsteinCMP

Upcoming Events

TBBC Case Study Group: Mondays – 5-7PM, Jaharis 508

Practice solving cases, gain insight and tips, and learn more about the field of consulting.

TBBC Tufts Biomedical Alumni Speed Networking Night: Th Apr 13 — 6-8PM, Sackler 114

TBBC, in collaboration with the Office of Alumni Relations will be hosting a speed networking night! Meet fellow students and Tufts alumni who are working in the biomedical field from across all of Tufts campuses and programs, including Sackler, Fletcher, Medical, Dental, Nutrition, and the Gordon Institute. Mingle with old friends and new. We look forward to seeing you! Food and drinks will be served at this facilitated networking event.

TBBC Biotech BUZZ with Lily Ting: F Apr 14 — 9AM, M&V Lobby (Stearns 108)

Dr. Lily Ting is a life scientist and entrepreneur with 12 years of experience in academia and industry. Lily received her PhD from New South Wales University in Sydney and a post doc in the Gygi Lab at Harvard Medical School. After her experience leading projects in the academic sphere, Lily worked in a business development role at Athletigen and is now an Associate at PureTech Health. PureTech is a venture creation firm focused on bringing innovative solutions to the fields of neuroscience, immunology, and gastrointestinal diseases. She is also an avid dragon boat racer and just won gold, silver, and bronze in Puerto Rico!

TBBC Consulting Seminar Series: ClearView Heathcare Partners: Tu Apr 18 — 5-6:30PM, Sackler 507

Representatives from ClearView Healthcare Partners will speak to students about consulting and ClearView’s Connect to ClearView program for advanced degree candidates. 

TBBC, the Sackler Dean’s Office, GSC “Sackler Speaks” Flash Talk Competition: M Apr 24 — 5PM, Sackler 114

A well-developed flash talk is an effective tool to quickly and easily communicate your work to others. These take time to develop and usually evolve over a series of iterations. Sackler students will have a chance to give their scientific flash talks before a judging panel and other students. All presenters will receive helpful feedback and compete for nice prizes. This will be a low-key, fun event with appetizers and beer, and a chance to network with other students and professionals.

Recent Events

TBBC Biotech Buzz with Joel Batson, PhD, of RA Capital

F Feb 24: TBBC hosted Joel Batson, Science Project Manager at RA Capital. Joel introduced students to a new web-based tool he is developing and offered students the opportunity to collaborate with him and his team.

TBBC Career Seminar: Teresa Broering, Director of R&D, Affinivax

Tu Apr 4: Teresa Broering, current Director of R&D at Affinivax, a Cambridage, MA-based company developing a next generation approach in vaccine technologies, and former Director of Immunology at AbVitro as well as Senior Director of Product Discovery at MassBiologics, joined us for a discussion of her career path and her current role with Affinivax, and the current state of the biotech industry.

April 2017, articles, arts & culture, Community, Events for Students

CMDB and Genetics Programs Come Together in Portland, Maine

For the first time, the Genetics and CMDB programs came together for a retreat in Portland, Maine for the snow and slush-filled weekend of April 1st. The retreat brought together students from different programs to interact and learn more about one another’s’ research, as well as students from different campuses. Both the Boston and the Bar Harbor Jackson Laboratories contingents made it to Portland to join the Scarborough Maine Medical Research Center Institute (MMCRI) folks for a weekend of science and camaraderie. Students and faculty gave brief talks on their work, followed by a poster session and a fantastic keynote speech on storytelling was given by Christine Gentry. Read on for details on the weekend, written by Jessica Elman (CMDB, Boston Campus), Jessica Davis-Knowlton (CMDB, MMCRI), and Alexander Fine (Genetics, JAX).  

We kicked off the retreat with a marathon of 16 talks given by students in year four and up from the CMDB and Genetics programs. Given the challenge to present a summary of their work in seven minutes or less, the students delivered with presentations that were brief but pointed. Three winners were selected by Philip HInds, Ira Herman, and Rajendra Kumar-Singh for their exceptional clarity, creativity, and concision.

In third place, Melissa LaBonty, a 5th year CMDB student in Pamela Yelick’s lab, presented on her work studying Fibrodysplasia Ossificans Progressiva (FOP). In this rare and severely understudied disease, an abnormal wound repair mechanism results in bone ossification in soft tissue after damage or injury. LaBonty is working with zebrafish to create a model of FOP, which will help to better characterize the disease and understand the underlying mechanisms that drive its progression. In her presentation, LaBonty spoke clearly and at an even pace, with assisting powerpoint slides that displayed only the most essential words: together this style helped keep the group focused on her story and contributed to her ranking as one of the best speakers of the day.

 

Siobhan McRee, a 5th year Genetics student in Philip Hinds’ lab, came in second among the student presenters. McRee talked about her work in which she is elucidating the roles of different Akt isoforms in BRAF-mutant melanoma. Though this cancer is initially responsive to the drug Vemurafenib, which specifically targets cells with a BRAF-mutation, cells with other driving mutations manage to survive the drug treatment and clonally expand, resulting in significant and potentially deathly relapse of disease. Ultimately, McRee’s work will help to better understand how the Akt signaling pathway is involved in this disease and may result in more therapeutically targetable molecules. McRee’s story logically built from general facts and understanding of BRAF melanoma to ultimately culminate on more specific data showing her findings thus far as well as their implications. Furthermore, her even pace and well-organized slides made her an especially great presenter that day.

Coming in first place was Kayla Gross, a 4th year CMDB student in Charlotte Kuperwasser’s lab. Gross’s work involves understanding how aging contributes to the breast cancer development, and why certain subtypes of breast cancer are more prevalent in the aging population. Given the prevalence of breast cancer, the impactfulness of Gross’ research is immediately obvious. She worked with an aging mouse model to characterize their mammary tissue as well as performed an RNAseq experiment to uncover molecular mechanisms that might be differentially expressed in young and aging mouse tissue. Gross presented her data in a logical progression, and used illustrative cartoons and animations to her advantage to keep her audience focused and to get her point across. Besides for her brilliant and captivating powerpoint, Gross stood out for her speaking style: she had clearly chosen her words to be concise and to the point, which allowed her to make the most of the seven minutes allotted to her.

All in all, the student presentations were remarkably impressive: in just seven minutes, all the participating students managed to convey the most critical and interesting components of their research. This was a great opportunity for everyone to learn a little bit more about what our colleagues are working on, as well as a chance to practice our “flash talk” skills, which will come in handy whether it’s at a job interview or at Thanksgiving table when your uncle asks you to explain what you’re doing in graduate school for the third time.

The Story Collider’s Christine Gentry, PhD as keynote

It was suggested by Terry Pratchett, Ian Stewart, and Jack Cohen in The Science of Discworld II: The Globe that perhaps Homo sapiens as a name for our species is a bit of a misnomer considering we are not omnipotent beings. They suggest Pan narrans, the storytelling ape, because we gain understanding by fitting facts into a larger narrative rather than collecting and storing millions of pieces of disparate information.

As communicators of new knowledge to the world (i.e. our scientific findings), it is important for us to keep the nature of our listeners in mind. In her keynote presentation to the retreat, Story Collider’s Christine Gentry, PhD encouraged us all to think about how to frame our narratives to be more approachable and demonstrated some methods of drawing in an audience.

She immediately captured our attention and sympathy by describing the challenges she faced in a wending career path that started with her geek excitement to bring a black widow spider to her Texas elementary school show-n’-tell, traversed through public outreach on the topic of zoology, and has landed at teacher/storyteller in Boston.

She required us to engage with her material by highlighting snippets of stories that we examined in small groups to find the element that made them compelling. We saw that admitting to vulnerability helps to humanize us to our audience in the story from a researcher who relies on fresh donor tissue, that self identity makes us more honest in the story from a researcher who decided not to cover her tattoos, and that we can surprise our audience by not sticking to script in the story from David who refused to tell the inspiration arising from conflict story that reporters sought to box him into. The thread tying all these stories together is that at the core they are about relationships with others, ourselves, our work, and with the larger community.

Perhaps the most memorable take-home point from her talk is that anecdotes do not equal stories. The response to most anecdotes is naturally “so what?” In order for an event or experience to be a story, it must have changed you: “I was callus, this event happened, and now I am more thoughtful” rather than “I am amazing, I did this, and I am still amazing!”

Scientific inquiry must be done in an objective manner and it is imperative that we remain unbiased as possible when we review scientific evidence, but there is room for us to inject our personalities into our presentations and relate our findings to the people who care. Now it remains to us to decide when to do so and to what degree.

On Sunday morning, we took a break from data and lectures; it was time to start working together. The purpose of this retreat was cross-program cooperation, and in our final event of the weekend, we put that goal into action. We separated into breakout sessions, not by program or campus, but by what we are interested in. These small group discussions were designed to get people together with various strengths and experiences to think about how to solve some of the challenges that graduate students face.

So what are graduate students at Sackler interested in discussing? The topics of these breakout sessions varied. Some sessions focused on day-to-day problems that a graduate student might face, like using CRISPR/Cas9 or selecting a sequencing platform. In the CRISPR discussion, participants came to the conclusion that there are no specific shared standards for all the applications of CRISPR and identified strategies to address potential off-target effects.

Other discussions centered on how to accomplish broader training goals, including grant writing, mentoring, and communicating in science. The grant writing section reviewed general writing strategies, like setting short-term, realistic goals, and shared a need for a formalized grant-writing course at Sackler. The mentoring/leadership session discussed existing programs at Sackler where a student can find a mentor, like the Tufts Mentoring Circles and the Tufts Biomedical Business Club. Students expressed a need for a more accessible alumni network, including cross-institutional resources. In the scientific communication group, students were urged to get on social media platforms like LinkedIn, Twitter, and ResearchGate.

In two of the largest breakout sessions, participants concentrated on solving larger scale problems: designing coursework for a modern graduate program in biology and bridging the gap between science and medicine. To help bridge the gap between scientific research and medicine at Tufts, the discussion group recommended that faculty members be identified that can connect labs with clinicians and tissue banks. In addition, access to a course that provides a basic orientation to clinical research would benefit many students at Sackler. In the session on coursework for a modern graduate program, one topic became the clear center of the discussion: computational biology! Whether students had struggled through teaching themselves or were currently stuck with a dataset they didn’t know how to analyze, everyone in the room agreed that coursework in computational biology was crucial for a graduate student’s success in modern biology. In addition to new coursework, students from both programs expressed a need for a revision and update of their first year coursework.

While all of the breakout sessions at the retreat were productive, they are meant to be starting points for continued discussion and collaboration. This retreat should be the springboard that leads to action across programs and institutions. Sackler students are lucky to be in programs that span multiple states, campuses, and research focuses. The cross talk between these groups will make each of our programs stronger and better prepare us for our careers in the future.

April 2017, articles, arts & culture

What Scientists Can Learn From Fiction Writers

Scientists don’t often think of themselves as writers. Our employment responsibilities do not include crafting characters or building worlds from words, nor investigating the latest political scandal, nor travelling the globe and composing reflections on our experiences. Yet, we do write: grants, reports, manuscripts. It is how we distribute our knowledge and the science we have done, because graphs and images and data have little impact if not shared. We write and revise as much as any journalist or novelist; still, writer isn’t an identity most scientists would primarily claim.

We are, though. Scientists are writers. Scientists are storytellers. Each graduate student, post-doc, faculty member has a story they are telling through their science. The scale and impact differs, but the fact remains: we must spin a tale convincing enough for our science to be funded, to be published, to matter. We are  writers, and we don’t even realize it.

I was trained to be a writer in the classical sense, specifically fiction writing. There were certain lessons that we learned over and over again, because they were fundamental to crafting even the most basic story. What fascinates me is that I have encountered these components informally in my graduate school training, just in the guise of doing good science.

We use basic story structure in writing articles: our beginnings ask a question, which we then try to answer in the middle, and our ends show how we have changed our little corner of the science world with our answer. There may even be a cliffhanger in there–alluding to a sequel coming soon to a journal near you!–if we’ve created even more questions with our answer. Grant writing uses a similar structure, with more emphasis on the cliffhanger. Leaving your reader on the edge of his seat, wondering what could come next, is something both scientists and fiction writers want (equally for the validation of having intrigued your audience and the satisfaction that such engagement often results in financial investment).

Show, don’t tell. Rather than telling a reader that a character is angry or sad, a writer should describe the character’s balled-up fists or tear-stained cheeks. For scientists, our equivalent of ‘telling’ is ‘data not shown’–and we all know how much we should avoid that. We do our showing in our figures. A scientist knows that the more data you can include, all the better. A scientist also knows that the more visually appealing your data is, the better it represents your conclusions. No one likes to read tables, right? Those data become so much more interesting as a pie chart, a graph, or a schematic. We show as much as we can, and tell as little as possible, because the best case scenario is when the data speaks for itself, instead of the scientist speaking for it.

Stories are much more interesting when they start in media res, or in the middle: no boring leadup, no extensive exposition. It is why publications often start with describing a hit or two they discovered from a screen, instead of the million little steps that led up to and happened during the screen itself. Good papers do that, and so does good fiction. The first Harry Potter book does not walk the reader through Harry’s childhood; it just starts right at the moment his life is about to change. Relevancy and immediacy are key components to telling any story, and scientists know and practice these principles to the best of their ability.

Crafting things out of thin air to make a story is a staple of fiction, but we know that as data fraud in the science world. The ‘characters’ in our scientific writing, the ‘plot’, the ‘setting’, the ‘rising action’, the ‘falling action’, all of those things have to be based on facts and evidence, on carefully planned and painstakingly executed experiments. They are based on reality. We know this; every scientist knows this. What we as scientists may not realize, however, is the extent to which fiction writing is also rooted in reality. Creating characters or worlds out of thin air is in actuality rarely done. The foundation of so many characters–ordinary or fantastical–come from experiences and observations within the writer’s own realm. It is a different way of collecting and representing evidence, a different way of asking or answering a question about the world. This reality-turned-fiction is one of the best ways a novel writer can build a sense of believability even in the most far-fetched fiction. It also builds trust between author and reader, one of the most important–and difficult–parts of fiction writing. Scientists have these components within their works as well, though constructed and strengthened in a different manner. Trust in science is built through executing proper and thorough controls, validating via different experimental methods, and considering (and hopefully, systematically eliminating) alternate theories or explanations. So regardless of the method in which they are built, that believability and that trust are critical components to any story, be it science or fiction.

Fiction writing, creative nonfiction writing, journalistic writing are all still very different beasts than scientific writing. Still, it would benefit scientists to focus less on the differences and more on where our often polarized fields actually do intersect. So much of our work is to provide convincing answers to difficult questions, and that type of evidence-based persuasion can be drastically more powerful if we use the same tools that traditional writers do. Scientists need to learn these tools as undergraduate and graduate students through formalized, structured, specified, and required coursework. That training will carry us, and our work, miles farther in graduate school and in our careers beyond. We need to be trained as writers, maybe as much as we are trained as scientists. Communicating our work in a persuasive and captivating manner is more important the ever, given the disturbing loss of faith in evidence-based arguments. We, as scientists, need to win that trust back, and to do so, we better be able to tell one hell of a story–to our funding institutions, to our public–about our science. For science to progress, we need our stories to be loud, to be spellbinding, to be believed and trusted by the public. We need to be writers, otherwise we might one day read a story about science that starts with once upon a time…